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[Source] The source of this record is MEDLINE®, a database of the U.S. National Library of Medicine.

Small molecule inhibitors of IkappaB kinase beta (IKKbeta), a key regulator of the NF-kappaB pathway, kill ABC DLBCL cells and hold promise for the treatment of this lymphoma type.

We conducted an RNA interference genetic screen to investigate potential mechanisms of resistance of ABC DLBCL cells to IKKbeta inhibitors.

We screened a library of small hairpin RNAs (shRNAs) targeting 500 protein kinases for shRNAs that would increase the killing of an ABC DLBCLcell line in the presence of a small molecule IKKbeta inhibitor.

Two independent shRNAs targeting IKKalpha synergized with the IKKbeta inhibitor to kill three different ABC DLBCLcell lines but were not toxic by themselves.

Surprisingly, IKKalpha shRNAs blocked the classical rather than the alternative NF-kappaB pathway in ABC DLBCL cells, as judged by inhibition of IkappaBalpha phosphorylation.

These results suggest that therapy for ABC DLBCL may be improved by targeting both IKKalpha and IKKbeta, possibly through CARD11 inhibition.

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It has been shown that GCB-DLBCL responds favorably to chemotherapy and expresses high levels of BCL6, a transcription repressor known to play a causative role in lymphomagenesis.

In comparison, ABC-DLBCL has lower levels of BCL6, constitutively activated nuclear factor-kappaB, and tends to be refractory to chemotherapy.

As a result, high-level STAT3 expression and activation are preferentially detected in ABC-DLBCL and BCL6-negative normal germinal center B cells.

Most importantly, inactivating STAT3 by either AG490 or small interference RNA in ABC-DLBCL cells inhibits cell proliferation and triggers apoptosis.

These phenotypes are accompanied by decreased expression of several known STAT3 target genes, including c-Myc, JunB, and Mcl-1, and increased expression of the cell- cycle inhibitor p27.

In addition to identifying STAT3 as a novel BCL6 target gene, our results define a second oncogenic pathway, STAT3 activation, which operates in ABC-DLBCL, suggesting that STAT3 may be a new therapeutic target in these aggressive lymphomas.

In this report we show that the BLIMP1/PRDM1 gene is inactivated by multiple mechanisms, including homozygous deletions, truncating or missense mutations, and transcriptional repression by constitutively active BCL6, in ∼53% of ABC-DLBCL.

In vivo, conditional deletion of Blimp1 in mouse B cells promotes the development of lymphoproliferative disorders recapitulating critical features of the human ABC-DLBCL.

Of 272 recurrent chromosomal aberrations that were associated with gene-expression alterations, 30 were used differentially by the DLBCL subtypes (P < 0.006).

An amplicon on chromosome 19 was detected in 26% of ABC DLBCLs but in only 3% of GCB DLBCLs and PMBLs.

Knockdown of SPIB by RNA interference was toxic to ABC DLBCLcell lines but not to GCB DLBCL, PMBL, or myeloma cell lines, strongly implicating SPIB as an oncogene involved in the pathogenesis of ABC DLBCL.

Deletion of the INK4a/ARF tumor suppressor locus and trisomy 3 also occurred almost exclusively in ABC DLBCLs and was associated with inferior outcome within this subtype.

FOXP1 emerged as a potential oncogene in ABC DLBCL that was up-regulated by trisomy 3 and by more focal high-level amplifications.

In GCB DLBCL, amplification of the oncogenic mir-17-92 microRNA cluster and deletion of the tumor suppressor PTEN were recurrent, but these events did not occur in ABC DLBCL.

Together, these data provide genetic evidence that the DLBCL subtypes are distinct diseases that use different oncogenic pathways.

These findings indicate that HDACIs increase CFZ activity in GC- and ABC-DLBCL cells sensitive or resistant to bortezomib through a JNK-dependent mechanism in association with DNA damage and inhibition of nuclear factor-kappaB activation.

Together, they support further investigation of strategies combining CFZ and HDACIs in DLBCL.

A potentially crucial difference between STAT3-high and STAT3-low ABC DLBCL is in the expression of bcl-2 family members.

Further mechanisms such as activation of nuclear factor-kappa B (NF-κB) activation seem to be responsible for upregulation of bcl-2 in ABC subtype of DLBCL with an adverse outcome.

As deregulation of STAT-3 pathway is known to play a critical role in ABC DLBCL and majority of the PCNSL are of the ABC subtype we studied the immunohistochemical expression of STAT-3 proteins in PCNSL along with other traditional markers (CD10, bcl-6, MUM-1 and bcl-2) in 17 cases of PCNSL occurring in immunocompetent patients.

Despite lack of STAT3 expression in all our cases, majority (70%) of the patients with bcl-2 positive PCNSL had an adverse outcome similar to that reported in systemic lymphomas of ABC subtype.

Based on our observations we propose that PCNSL represents a distinct subset of ABCdiffuse large B-cell lymphomas with low STAT3 expression and perhaps mechanisms other than interaction of STAT-3 and NF-κB pathways may play a role in upregulation of bcl-2 in PCNSL.

To the best of our knowledge expression of STAT-3 protein in PCNSL which represents a distinct anatomical subset of ABC DLBCL with a dismal prognosis has not been studied before.

[Source] The source of this record is MEDLINE®, a database of the U.S. National Library of Medicine.

[Title] BCL2 expression is a prognostic marker for the activated B-cell-like type of diffuse large B-cell lymphoma.

BACKGROUND: The role of BCL2 as a predictor of survival in diffuse large B-cell lymphoma (DLBCL) is controversial.

DLBCL is heterogeneous, and the expression of BCL2 is variable within the two major subgroups of DLBCL, germinal center B-cell-like (GCB) and activated B-cell-like (ABC) DLBCL, as well as primary mediastinal DLBCL.

PATIENTS AND METHODS: In this study, we investigated the correlation of BCL2 expression with survival in the two major subgroups of DLBCL, as well as the mechanisms of BCL2 expression.

RESULTS: There was no significant correlation between BCL2 protein expression and overall survival within the GCB subgroup, but BCL2 expression had a significant adverse effect on overall survival within the ABC subgroup (P = .008).

The t(14;18) was frequently observed in the GCB subgroup and was highly associated with BCL2 expression.

Patients with ABC DLBCL did not exhibit t(14;18) but had a markedly higher frequency of chromosome 18q21 amplification, on which BCL2 resides.

Thus, alternative mechanisms such as 18q21 amplification or activation of the nuclear factor-kappa B pathway, as reported previously, seem to be mainly responsible for the upregulation of BCL2 expression in the ABC subgroup.

CONCLUSION: Treating all DLBCL as a single entity ignores the mechanistic differences in BCL2 upregulation and obscures the prognostic significance of BCL2 expression.

Hence, the significance of BCL2 and other biomarkers should be assessed in the context of DLBCL subgroups in future studies.

Within diffuse large B-cell lymphomas (DLBCL), two major molecular subtypes, the activated B-cell-like (ABC) and the germinal center B-cell-like (GCB) DLBCL, can be defined.

In retrospective analyses, the molecular phenotype of ABC DLBCL is associated with inferior survival.

Gene expression profiling furthermore allows the molecular separation of Burkitt lymphoma (BL) from DLBCL and reveals a Burkitt-specific signature which is also expressed by a subset of tumors that are currently classified as DLBCL.

Whether patients with a DLBCL displaying a Burkitt-specific gene expression signature may benefit from alternative therapeutic approaches will have to be determined in future prospective clinical trials.

In follicular lymphoma (FL), two outcome-related signatures, termed Immune response 1 (IR1) and Immune response 2 (IR2), have been identified by gene expression profiling, indicating a significant role of the microenvironment in tumor development and progression.

In mantle cell lymphoma (MCL), a gene expression-based proliferation signature of 20 different genes was identified that is able to predict survival of MCL patients in a linear fashion.

Future efforts will have to be directed towards the translation of relevant molecular diagnostic and prognostic markers derived from the wealth of gene expression data into clinical tests and towards the development of novel, targeted therapies.

[Source] The source of this record is MEDLINE®, a database of the U.S. National Library of Medicine.

[Title] Addition of rituximab to standard chemotherapy improves the survival of both the germinal center B-cell-like and non-germinal center B-cell-like subtypes of diffuse large B-cell lymphoma.

PURPOSE: Diffuse large B-cell lymphoma (DLBCL) includes at least two prognostically important subtypes (ie, germinal center B-cell-like [GCB] and activated B-cell-like [ABC] DLBCL), which initially were characterized by gene expression profiling and subsequently were confirmed by immunostaining.

However, with the addition of rituximab to standard chemotherapy, the prognostic significance of this subclassification of DLBCL is unclear.

[Source] The source of this record is MEDLINE®, a database of the U.S. National Library of Medicine.

The isoforms TAp63 and TAp73 transactivate p53 target genes and induce apoptosis, whereas the isoforms DeltaNp63 and DeltaNp73 lack transactivation and might have dominant-negative effects in p53 family members. p63 is expressed in germinal centre lymphocytes and can be related to the development of the lymphoma, but the prognostic significance of its expression in the survival of patients with diffuse large B-cell lymphoma (DLBCL) remains unclear.

METHODS: CD10, Bcl-6 and IRF4 expression were retrospectively evaluated by IHC in 73 samples of high-intermediate and high risk DLBCL and were used to divide the lymphomas into subgroups of germinal centre B-cell-like (GCB) and activate B-cell-like (ABC) DLBCL.

Similarly, p63 expression was evaluated by IHC and the results were compared with subgroups of DLBCL origin and with the survival rates for these patients.

RESULTS: p63 was expressed in more than 50% of malignant cells in 11 patients and did not show correlation with subgroups of GCB-likeDLBCL or ABC-likeDLBCL, but p63(+) patients had better disease-free survival (DFS) than those who were negative (p = 0.01).

CONCLUSIONS: p63(+) high-intermediate and high risk DLBCL patients have a better DFS than negative cases.

[Source] The source of this record is MEDLINE®, a database of the U.S. National Library of Medicine.

To elucidate the mechanisms underlying chromosomal translocations in diffuse large B cell lymphoma (DLBCL), we investigated the nature and extent of immunoglobulin class switch recombination (CSR) in these tumors.

Major differences between these two subtypes include genetic aberrations leading to constitutive NF-κB activation and interference with terminal B cell differentiation through BLIMP1 inactivation, observed in ABC- but not GCB-DLBCL.

Using conditional gain-of-function and/or loss-of-function mutagenesis in the mouse, we show that constitutive activation of the canonical NF-κB pathway cooperates with disruption of BLIMP1 in the development of a lymphoma that resembles human ABC-DLBCL.

Our work suggests that both NF-κB signaling, as an oncogenic event, and BLIMP1, as a tumor suppressor, play causal roles in the pathogenesis of ABC-DLBCL.

Thus, our results indicate a growth-promoting role for MALT1 paracaspase activity in ABC-DLBCL and suggest that a pharmacological MALT1 protease inhibition could be a promising approach for lymphoma treatment.

[Source] The source of this record is MEDLINE®, a database of the U.S. National Library of Medicine.

Diffuse large B-cell lymphoma (DLBCL), the most common form of lymphoma in adulthood, comprises multiple biologically and clinically distinct subtypes including germinal centre B-cell-like (GCB) and activated B-cell-like (ABC) DLBCL.

Gene expression profile studies have shown that its most aggressive subtype, ABC-DLBCL, is associated with constitutive activation of the NF-kappaB transcription complex.

However, except for a small fraction of cases, it remains unclear whether NF-kappaB activation in these tumours represents an intrinsic program of the tumour cell of origin or a pathogenetic event.

Here we show that >50% of ABC-DLBCL and a smaller fraction of GCB-DLBCL carry somatic mutations in multiple genes, including negative (TNFAIP3, also called A20) and positive (CARD11, TRAF2, TRAF5, MAP3K7 (TAK1) and TNFRSF11A (RANK)) regulators of NF-kappaB.

Thus, our results demonstrate that NF-kappaB activation in DLBCL is caused by genetic lesions affecting multiple genes, the loss or activation of which may promote lymphomagenesis by leading to abnormally prolonged NF-kappaB responses.

[Source] The source of this record is MEDLINE®, a database of the U.S. National Library of Medicine.

[Title] Cooperative signaling through the signal transducer and activator of transcription 3 and nuclear factor-{kappa}B pathways in subtypes of diffuse large B-cell lymphoma.

The activated B cell-like (ABC) subgroup of diffuse large B-cell lymphoma (DLBCL) is characterized by constitutive activation of the nuclear factor-kappaB (NF-kappaB) pathway.

In this study, we showed that the NF-kappaB pathway induced the expression of the cytokines interleukin (IL)-6 and IL-10 in ABC DLBCLcell lines, which also have high levels of total and phosphorylated signal transducer and activator of transcription (STAT) 3 protein, suggesting autocrine signaling.

Using RNA interference for STAT3, we defined a gene expression signature of IL-6 and IL-10 signaling through STAT3.

Based on this signature, we constructed a molecular predictor of STAT3 signaling that defined a subset of ABC DLBCL tumors with high expression of STAT3, IL-6, and/or IL-10 and their downstream targets.

Although the STAT3-high and STAT3-low subsets had equivalent expression of genes that distinguish ABC DLBCL from germinal center B cell-likeDLBCL, STAT3-high ABC DLBCLs had higher expression of signatures that reflected NF-kappaB activity, proliferation, and glycolysis.

A small-molecule inhibitor of Janus kinase signaling, which blocked STAT3 signature expression, was toxic only for ABC DLBCL lines and synergized with an inhibitor of NF-kappaB signaling.

These findings suggest that the biological interplay between the STAT3 and NF-kappaB pathways may be exploited for the treatments of a subset of ABC DLBCLs.

[Source] The source of this record is MEDLINE®, a database of the U.S. National Library of Medicine.

To begin to address this issue in B-cells, we used BeadArray assays to survey the methylation status of over 1,500 cancer-related CpG loci in two molecular subtypes of diffuse large B-cell lymphoma (ABC-DLBCL and GCB-DLBCL) and cognate normal B-cell populations.

We identified 81 loci that showed frequent de novo DNA methylation in GCB-DLBCL and 67 loci that showed frequent de novo DNA methylation in ABC-DLBCL.

All candidate loci in GCB-DLBCL are proximal to genes that are poorly expressed or silent in purified normal germinal center (GC) B-cells.

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The DLBCL subgroups differed significantly in the frequency of particular chromosomal aberrations.

ABC-DLBCL had frequent trisomy 3, gains of 3q and 18q21-q22, and losses of 6q21-q22, whereas GCB-DLBCL had frequent gains of 12q12, and PMBCL had gains of 9p21-pter and 2p14-p16.

Parallel analysis of CGH alterations, locus-specific gene-expression profiles, and global gene-expression signatures revealed that DNA amplifications and gains had a substantial impact on the expression of genes in the involved chromosomal regions, and some genes were overexpressed in a DLBCL subgroup-specific fashion.

Unexpectedly, specific chromosomal alterations were associated with significant changes in gene-expression signatures that reflect various aspects of lymphoma cell biology as well as the host response to the lymphoma.

[Source] The source of this record is MEDLINE®, a database of the U.S. National Library of Medicine.

A role for B-cell-receptor (BCR) signalling in lymphomagenesis has been inferred by studying immunoglobulin genes in human lymphomas and by engineering mouse models, but genetic and functional evidence for its oncogenic role in human lymphomas is needed.

Here we describe a form of 'chronic active' BCR signalling that is required for cell survival in the activated B-cell-like (ABC) subtype of diffuse large B-cell lymphoma (DLBCL).

The signalling adaptor CARD11 is required for constitutive NF-kappaB pathway activity and survival in ABC DLBCL.

Roughly 10% of ABC DLBCLs have mutant CARD11 isoforms that activate NF-kappaB, but the mechanism that engages wild-type CARD11 in other ABC DLBCLs was unknown.

An RNA interference genetic screen revealed that a BCR signalling component, Bruton's tyrosine kinase, is essential for the survival of ABC DLBCLs with wild-type CARD11.

In addition, knockdown of proximal BCR subunits (IgM, Ig-kappa, CD79A and CD79B) killed ABC DLBCLs with wild-type CARD11 but not other lymphomas.

The BCRs in these ABC DLBCLs formed prominent clusters in the plasma membrane with low diffusion, similarly to BCRs in antigen-stimulated normal B cells.

Somatic mutations affecting the immunoreceptor tyrosine-based activation motif (ITAM) signalling modules of CD79B and CD79A were detected frequently in ABC DLBCL biopsy samples but rarely in other DLBCLs and never in Burkitt's lymphoma or mucosa-associated lymphoid tissue lymphoma.

In 18% of ABC DLBCLs, one functionally critical residue of CD79B, the first ITAM tyrosine, was mutated.

ABC DLBCL has a worse survival after upfront chemotherapy and is characterized by constitutive activation of the antiapoptotic nuclear factor-kappa B (NF-kappaB) pathway, which can inhibit chemotherapy.

We hypothesized that inhibition of NF-kappaB might sensitize ABC but not GCB DLBCL to chemotherapy and improve outcome.

As the proteasome inhibitor bortezomib can inhibit NF-kappaB through blocking IkappaBalpha degradation, we investigated bortezomib alone followed by bortezomib and doxorubicin-based chemotherapy in recurrent DLBCL.

We report here that the BLIMP1 gene is inactivated by structural alterations in 24% (8 out of 34) activated B cell-like diffuse large cell lymphoma (ABC-DLBCL), but not in GC B cell-like (n = 0/37) or unclassified (n = 0/21) DLBCL.

These results indicate that a sizable fraction of ABC-DLBCL carry an inactive BLIMP1 gene, and suggest that the same gene is inactivated by epigenetic mechanisms in an additional large number of cases.

These DLBCL subgroups arise from different stages of normal B-cell differentiation, utilize distinct oncogenic mechanisms, and differ in their ability to be cured by chemotherapy.

ABC DLBCL and PMBL depend upon constitutive activation of the NF-kappaB pathway for their survival but GCB DLBCL does not, demonstrating that this pathway is a potential therapeutic target for certain DLBCL subgroups.

In DLBCL, mantle cell lymphoma, and follicular lymphoma, gene expression profiling has also been used to create gene expression-based models of survival, which have identified the biological characteristics of the tumors that influence their clinical behavior.

In mantle cell lymphoma, the length of survival following diagnosis is primarily influenced by the tumor proliferation rate, which can be quantitatively measured by a proliferation gene expression "signature."

Based on this accurate measure, the proliferation rate can now be viewed as an integration of several oncogenic lesions that each increase progression from the G1 to the S phase of the cell cycle.

In DLBCL and follicular lymphoma, gene expression profiling has revealed that the molecular characteristics of non-malignant tumor-infiltrating immune cells have a major influence on the length of survival.

[Source] The source of this record is MEDLINE®, a database of the U.S. National Library of Medicine.

[Title] Small molecule inhibitors of IkappaB kinase are selectively toxic for subgroups of diffuse large B-cell lymphoma defined by gene expression profiling.

Constitutive activation of the NF-kappaB pathway is required for survival of the activated B cell-like (ABC) subgroup of diffuse large B-cell lymphoma (DLBCL).

Here we show that a small molecule IkappaB kinase (IKK) inhibitor, PS-1145, and related compounds are toxic for ABC DLBCLcell lines but not for cell lines derived from the other prevalent form of DLBCL, germinal center B cell-likeDLBCL.

Treatment of ABC lines with these inhibitors rapidly induced a series of gene expression changes that were attributable to cessation of constitutive IKK activity, similar to changes induced by acute expression of genetic inhibitors of NF-kappaB, confirming the effectiveness and specificity of this compound.

Before cell death, inhibition of IKK also induced features of apoptosis and an arrest in the G1 phase of the cell cycle.

In the presence of tamoxifen, p65-ERD reversed the toxicity of IKK inhibition and restored expression of many NF-kappaB target genes.

Another subgroup of DLBCL, primary mediastinal B-cell lymphoma (PMBL), also expresses NF-kappaB target genes, and treatment of a PMBL cell line with an IKK inhibitor was toxic and induced gene expression changes of a distinct group of NF-kappaB target genes.

These studies validate the NF-kappaB pathway as a promising therapeutic target in ABC DLBCL, PMBL, and other lymphomas that depend on the activity of NF-kappaB for survival and proliferation.

[Source] The source of this record is MEDLINE®, a database of the U.S. National Library of Medicine.

Mucosa-associated lymphoid tissue transformation protein 1 (MALT1) is a proto-oncogene that contributes to tumorigenesis in diffuse large B-cell lymphoma (DLBCL) of the activated B-cell (ABC) subtype, the least curable subtype of DLBCL.

Here we report that MALT1 is constitutively active in DLBCL lines of the ABC but not the GCB subtype.

Inhibition of the MALT1 proteolytic activity led to reduced expression of growth factors and apoptosis inhibitors, and specifically affected the growth and survival of ABC DLBCL lines.

These results demonstrate a key role for the proteolytic activity of MALT1 in DLBCL of the ABC subtype, and provide a rationale for the development of pharmacological inhibitors of MALT1 in DLBCL therapy.

[Source] The source of this record is MEDLINE®, a database of the U.S. National Library of Medicine.

[Title] Overexpression of an activated REL mutant enhances the transformed state of the human B-lymphoma BJAB cell line and alters its gene expression profile.

Overexpression of REL is acutely transforming in chicken lymphoid cells, but has not been shown to transform any mammalian lymphoid cell type.

In this report, we show that overexpression of a highly transforming mutant of REL (RELDeltaTAD1) increases the oncogenic properties of the human B-cell lymphoma BJAB cell line, as shown by increased colony formation in soft agar, tumor formation in SCID (severe combined immunodeficient) mice, and adhesion.

Overexpression of RELDeltaTAD1 in BJAB cells has transformed the gene expression profile of BJAB cells from that of a germinal center B-cell subtype of diffuse large B-cell lymphoma (DLBCL) (GCB-DLBCL) to that of an activated B-cell subtype (ABC-DLBCL), as evidenced by increased expression of many ABC-defining mRNAs.

Upregulated genes in BJAB-RELDeltaTAD1 cells include several NF-kappaB targets that encode proteins previously implicated in B-cell development or oncogenesis, including BCL2, IRF4, CD40 and VCAM1.

The cell system we describe here may be valuable for further characterizing the molecular details of REL-induced lymphoma in humans.

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Targeted resequencing studies have revealed mutations in various genes encoding proteins in the NF-kappaB pathway that contribute to the activated B-cell (ABC) DLBCL subtype, but thus far few GCB-specific mutations have been identified.

These mutations, which result in the replacement of a single tyrosine in the SET domain of the EZH2 protein (Tyr641), occur in 21.7% of GCB DLBCLs and 7.2% of FLs and are absent from ABC DLBCLs.

A comparison of genome profiles of distinct subgroups of DLBCL demonstrated that (1) ABC DLBCL is characterized by gain of 3q, 18q, and 19q and loss of 6q and 9p21, and GCB DLBCL is characterized by gain of 1q, 2p, 7q, and 12q;.

(2) the genomic imbalances characteristic of the CD5(+) and CD5(-)CD10(+) groups were similar to those of the ABC and GCB types, respectively.

These findings suggest that CD5(+) and CD5(-)CD10(+) subgroups are included, respectively, in the ABC and GCB types.

Finally, when searching for genomic imbalances that affect patients' prognosis, we found that 9p21 loss (p16(INK4a) locus) marks the most aggressive type of DLBCL.

[Source] The source of this record is MEDLINE®, a database of the U.S. National Library of Medicine.

Diffuse large B-cell lymphoma (DLBCL) forms a heterogeneous collection of aggressive non-Hodgkin's Lymphoma in which three principle classes of neoplasia have been defined according to gene expression and immunophenotyping studies.

A series of 155 DLBCL treated uniformly with anthracycline therapy in clinical trials, were stratified upon the basis of common biomarker expression with combination immunophenotype being related to patient overall survival.

Stratification of tumours with respect to combined expression profiles of the three biological markers (CD10, Bcl-6 and MUM-1) revealed six groups showing significant differences in survival (p=0.014).

The greatest difference resided between distinct populations of germinal centre (GC) cell tumours; the first being CD10-, Bcl-6+, MUM-1- and the second CD10+ Bcl-6+ MUM-1+ (p=0.002).

The first of these comprised two patient sub-populations with GC-like tumours together with one sub-population of NGC/ABC, the second two sub-populations of ABC-like tumours, and the final a single group of GC-like tumours associated with optimal long-term survival.

[Source] The source of this record is MEDLINE®, a database of the U.S. National Library of Medicine.

The FOXP1 forkhead transcription factor is targeted by recurrent chromosome translocations in several subtypes of B-cell non-Hodgkin lymphomas, where high-level FOXP1 protein expression has been linked to a poor prognosis.

Western blotting studies of diffuse large B-cell lymphoma (DLBCL) cell lines unexpectedly identified the atypical high-level expression of 2 smaller, 60 to 65 kDa, FOXP1 isoforms in all 5 of those with the activated B cell (ABC)-likeDLBCL subtype and in a subgroup of primary DLBCL.

The anti-FOXP1 (JC12) monoclonal antibody cannot distinguish FOXP1 isoforms by immunohistochemistry, a finding that may be clinically relevant as high-level expression of the full-length FOXP1 protein was observed in some germinal center-derived DLBCLs.

These transcripts and the smaller protein isoforms were induced as a consequence of normal B-cell activation, which thus represents an additional mechanism for up-regulating FOXP1 expression in lymphomas.

The expression of potentially oncogenic smaller FOXP1 isoforms may resolve the previously contradictory findings that FOXP1 represents a favorable prognostic marker in breast cancer and an adverse risk factor in B-cell lymphomas.

[Source] The source of this record is MEDLINE®, a database of the U.S. National Library of Medicine.

The microRNAs are endogenous, non-coding RNAs that play key roles in a range of pathophysiological processes by up- or down-regulating gene expression.

Diffuse large B-cell lymphoma (DLBCL) is an aggressive non-Hodgkin's lymphoma with a heterogeneous biology, which has impeded the clinical assessment of patients.

Recent immunohistochemical approaches have identified two different prognostic groups: the more indolent germinal centre (GC)- and the higher risk activated B-cell (ABC)-like phenotypes.

The present study uses microRNA profiling and a number of well-characterised B-cell lymphoma cell lines to identify microRNA signatures that are correctly assigned to the DLBCL prognostic subgroups and distinguish DLBCL from other more indolent lymphoma, including follicular lymphoma (FL).

We identified a 9 microRNA signature that discriminated between ABC- and GC-likeDLBCL.

This included 3 newly identified microRNAs, not previously associated with DLBCL and predicted to target genes that are de-regulated in lymphoma.

DLBCL was distinguished from FL by 4 microRNAs and a total of 18 microRNAs were identified that differentiated between all lymphoma and control populations.

In conclusion, the present study identified a microRNA signature that correctly classified GC and ABC phenotypes in DLBCLcell lines.

Concomitant or sequential exposure to non- or minimally toxic concentrations of bortezomib or other proteasome inhibitors and either HA14-1 or gossypol resulted in a striking increase in Bax/Bak conformational change/translocation, cytochrome c release, caspase activation and synergistic induction of apoptosis in both GC- and ABC-type cells.

EXPERIMENTAL DESIGN: We investigated the effect of different inhibitors of NF-kappaB on classic Hodgkin's lymphoma, multiple myeloma, and activated B-cell-like diffuse large B-cell lymphoma cell lines harboring different molecular defects in apoptosis signaling both quantitatively and qualitatively.

Surprisingly, 15-deoxy-Delta12,14-prostaglandin J(2) and the IkappaB kinase inhibitor curcumin both reduced nuclear levels of p65 in cell lines lacking IkappaBalpha, suggesting that inhibition of nuclear translocation of NF-kappaB can occur in the absence of IkappaBalpha.

CONCLUSIONS: These results show that molecular defects in apoptotic signaling, such as IkappaBalpha mutations, can be circumvented by targeting NF-kappaB through inhibition of the IkappaB kinase complex followed by induction of apoptosis in classic Hodgkin's lymphoma, multiple myeloma, and activated B-cell-like diffuse large B-cell lymphoma.

[Source] The source of this record is MEDLINE®, a database of the U.S. National Library of Medicine.

[Title] Usefulness of immunohistochemistry in identification of prognostically important subgroups (GCB and ABC) in a heterogeneous group of diffuse large B-cell lymphomas--a review article.

Although diffuse large B cell lymphomas (DLBCL) are considered in the WHO classification a specific histopathological type, their diversity in the clinical features, morphology and molecular aberrations strongly suggest that these tumors represent a heterogeneous group of neoplasms rather than a single clinicopathological entity.

Although it has been proven that gene expression profiling using cDNA microarrays could identify prognostically important subgroup of DLBCL: germinal center B-cell (GCB)-likeDLBCL and activated B-cell (ABC)-likeDLBCL, this method is impractical as a clinical tool.

Employing various immunohistochemical antibodies, such as CD10, CD138, anti-Bcl-2, anti-Bcl-6, MUM1 and anti-p53, several groups have aimed at subclassifying DLBCL into the GCB and ABC subgroups with comparable differences in clinical behavior.

This review summarizes these data and indicates their impact on DLBCL classification.

[Source] The source of this record is MEDLINE®, a database of the U.S. National Library of Medicine.

[Title] Members of the glutathione and ABC-transporter families are associated with clinical outcome in patients with diffuse large B-cell lymphoma.

Standard chemotherapy fails in 40% to 50% of patients with diffuse large B-cell lymphoma (DLBCL).

We examined the expression of genes in the glutathione (GSH) and ATP-dependent transporter (ABC) families in 2 independent tissue-based expression microarray datasets obtained prior to therapy from patients with DLBCL.

Recursive partitioning identified a group of patients with low-level expression of GPX1 and multidrug resistance 1 (MDR1; ABCB1) without early treatment failures and with superior dOS (P < .001).

Overall, our findings suggest an important association of oxidative-stress defense and drug elimination with treatment failure in DLBCL and identify GPX1 and ABCB1 as potentially powerful biomarkers of early failure and disease-specific survival.

[Source] The source of this record is MEDLINE®, a database of the U.S. National Library of Medicine.

AIMS: Tumour necrosis factor (TNF)-receptor associated factor 2 (TRAF2) is an adaptor molecule involved in nuclear factor (NF)-kappaB activation, which is characteristic of in vitro activated B-cell (ABC)-like diffuse large B-cell lymphomas (DLBCL) and may result in expression of anti-apoptotic genes and poor response to chemotherapy.

The aim was to determine whether TRAF2 is preferentially expressed in ABC-likeDLBCL, and whether expression correlates with clinical outcome.

METHODS AND RESULTS: TRAF2 was expressed in nine of 20 tested ABC-like DLBCLs and in only one of 13 tested germinal centre B-lymphocyte (GCB)-like DLBCLs.

High TRAF2 expression was correlated with high International Prognostic Index at time of presentation, high chance of relapse and short progression-free survival time in 44 tested DLBCLs.

[Source] The source of this record is MEDLINE®, a database of the U.S. National Library of Medicine.

The most common type of primary testicular lymphoma is diffuse large B-cell type, which has a poor prognosis relative to other extra-nodal diffuse large B-cell lymphomas (DLBCL).

These constitute a heterogeneous group of lymphomas with germinal center B-cell-like and activated B-cell-like subtypes.

Such a distinction theoretically utilizes the immunohistochemical expression of CD10, Bcl-6, and MUM1.

The purpose of this study was that we could stratify primary testicular lymphoma of diffuse large B-cell type according to this scheme, and further elucidate the reason why primary testicular diffuse large B-cell lymphoma possesses a poor clinical outcome.

[Source] The source of this record is MEDLINE®, a database of the U.S. National Library of Medicine.

[Title] A cell-based assay for IkappaBalpha stabilization using a two-color dual luciferase-based sensor.

A cell-sensor assay for stabilization of IkappaBalpha was developed in the activated B cell-like diffuse large B-cell lymphoma cell line OCI-Ly3.

This cell line expresses known nuclear factor kappaB (NFkappaB) target genes due to high constitutive activity of IkappaB kinase (IKK), which phosphorylates the protein IkappaBalpha leading to proteasomal degradation of IkappaBalpha and activation of NFkappaB.

The cell-sensor assay uses green and red light-emitting beetle luciferases, with the green luciferase fused to IkappaBalpha (IkappaBalpha-CBG68) and the red luciferase (CBR) present in its native state.

The IkappaBalpha-CBG68 reporter functions as a sensor of IKK and proteasome activity, while CBR serves to normalize for cell number and nonspecific effects.

[Source] The source of this record is MEDLINE®, a database of the U.S. National Library of Medicine.

In the European Organization for Research and Treatment of Cancer (EORTC) classification 2 types of primary cutaneous large B-cell lymphoma (PCLBCL) are distinguished: primary cutaneous follicle center cell lymphomas (PCFCCL) and PCLBCL of the leg (PCLBCL-leg).

To establish a molecular basis for this subdivision in the EORTC classification, we investigated the gene expression profiles of 21 PCLBCLs by oligonucleotide microarray analysis.

[Source] The source of this record is MEDLINE®, a database of the U.S. National Library of Medicine.

The prevalence and regulation of p38 mitogen activated protein kinase (MAPK) expression in human lymphomas have not been extensively studied.

In order to elucidate the role of p38 MAPK in lymphomagenesis, we examined the expression of native and phosphorylated p38 (p-p38) MAPK in cell lines derived from human hematopoietic neoplasms including B cell lymphoma-derived cell lines using Western blot analysis.

Our results show that the expression of p38 MAPK was up-regulated in most of the cell lines as compared with peripheral blood lymphocytes, while the expression of p-p38 MAPK was more variable.

Interleukin-4 (IL-4) induced a dose-dependent increase in the expression of p-p38 MAPK (1.6- to 2.8-fold) in cell lines derived from activated B cell-like diffuse large B cell lymphoma (DLBCL) but not those from germinal center-likeDLBCL.

The in vitro kinase activity of p38 MAPK, however, was induced (1.6- to 3.2-fold) in all five cell lines by IL-4.

Quantitative fluorescent RT-PCR demonstrated that all four isoforms of p38 MAPK gene were expressed in the lymphoma cell lines, with p38gamma and p38beta isoforms being predominant.

IL-4 stimulation increased the expression of beta, gamma, and delta isoforms but not alpha isoform in two cell lines.

In conclusion, there is constitutive expression and activation of p38 MAPK in a large number of B-lymphoma-derived cell lines and primary lymphoma tissues, supportive of its role in lymphomagenesis.

The differential IL-4 regulation of p38 MAPK expression in cell lines derived from DLBCL may relate to the cellular origin of these neoplasms.

[Source] The source of this record is MEDLINE®, a database of the U.S. National Library of Medicine.

Morphologic features of Burkitt lymphoma (BL) and diffuse large B-cell lymphoma (DLBCL) overlap.

We tested a panel of 8 germinal center (GC) and activated B-cell (ABC) markers for their ability to separate BL and DLBCL.

We diagnosed 16 BL and 39 DLBCL cases from 21 patients with AIDS and 34 without AIDS based on traditional morphologic criteria, Ki-67 proliferative index, and c-myc rearrangement (fluorescence in situ hybridization).

After immunohistochemically staining tissue microarrays of BL and DLBCL for markers of GC (bcl-6, CD10, cyclin H) and ABC (MUM1, CD138, PAK1, CD44, bcl-2), we scored each case for the percentage of positive cells.

For comparison, we plotted the sum of the GC scores and ABC scores for each case as x and y data points.

This revealed a high-GC/low-ABC group and a low-GC/high-ABC group that were associated significantly with morphologic diagnosis (P < .001).

Protein expression of multiple GC and ABC markers can separate BL and DLBCL.

[Source] The source of this record is MEDLINE®, a database of the U.S. National Library of Medicine.

OBJECTIVE: Hierarchical clusterings of diffuse large B-cell lymphoma (DLBCL) based on gene expression signatures have previously been used to classify DLBCL into Germinal Center B-cell (GCB) and Activated B-cell (ABC) types.

To examine if it was feasible to perform a cross-platform validation on the Affymetrix HG-U133A oligonucleotide arrays and improve the classification, we determined the expression profiles of pretreatment, diagnostic samples from 52 primary nodal DLBCL.

In this way, three subtypes, including the GCB type (n = 20), the ABC type (n = 25) and an intermediate group, Type-3 (n = 5), were distinguished.

The CD10 and Bcl-6 expression as well as t(14;18) translocation were prevalent, but not exclusive to the GCB type.

By contrast, MUM1 was only expressed in the ABC and in Type-3 samples.

The 5-year survival was similar between the groups, but GCB patients showed a better initial response to CHOP or CHOP-like regimens than the remaining patients and tended to have less advanced disease and lower IPI scores.

As a next step, an improved set of classifier genes was generated by analysis of 34 patients that were consistently classified as GCB or ABC in the above analyses.

CONCLUSION: We conclude that gene expression profiling with Affymetrix Genechips is efficient to distinguish between GCB and ABC types of DLBCL and that these are likely to represent separate biological entities.

The Genechip platform is highly standardised and therefore useful for future prospective investigations to establish the value of gene expression profiling in the clinical management of DLBCL.

[Source] The source of this record is MEDLINE®, a database of the U.S. National Library of Medicine.

[Title] The rGel/BLyS fusion toxin inhibits diffuse large B-cell lymphoma growth in vitro and in vivo.

Diffuse large B-cell lymphoma (DLBCL) is an aggressive subtype of B-cell non-Hodgkin lymphoma (NHL) and accounts for 30%to 40%of NHL.

Molecules targeting nuclear factor-kappaB (NF-kappaB) are expected to be of therapeutic value in those tumors where NF-kappaB seems to play a unique survival role such as activated B-cell (ABC)-subtype DLBCL.

In this study, we examined this fusion toxin for its ability to suppress DLBCL growth in vitro and in vivo. rGel/BLyS was specifically cytotoxic to DLBCL lines expressing all three BLyS receptors and constitutively active NF-kappaB.

Overexpression of microRNA-155 (miR-155), measured either at the primary (BIC gene) or mature transcript level, was recently described in diffuse large B-cell lymphomas (DLBCL).

These studies have been limited in size, however, and have not attempted to link miR-155 expression to that of putative target genes.

To start to address these issues, we examined a collection of 22 well-characterized DLBCLcell lines.

The expression of miR-155 is heterogeneous in these cell lines and associates with NF-kappaB activity.

We found that the expression of the primary miR-155 transcript reliably reflects that of the functional mature miR-155.

Because many gene array platforms include probe sets for the primary miR-155 sequences, these findings allowed us to confidently examine large array-based expression datasets of primary DLBCLs in the context of miR-155 levels.

Our investigation revealed that miR-155 expression segregates with specific molecular subgroups of DLBCL and it is highest in activated B-cell (ABC)-type lymphomas.

These tumors are characterized by constitutive activation of NF-kappaB signals, which supports the data derived from our cell lines.

More importantly, using supervised learning algorithms, we identified a robust gene signature driven by the differential expression of miR-155.

Our data start to unveil the genome-wide effects of miR-155 expression in DLBCL and indicate the utility of this strategy in the identification and validation of miRNA target genes.

[Source] The source of this record is MEDLINE®, a database of the U.S. National Library of Medicine.

Diffuse large B-cell lymphomas (DLBCLs) can be subclassified into germinal center B-cell (GCB)-like and activated B-cell (ABC)-like tumors characterized by long and short survival, respectively.

In contrast to ABC-likeDLBCL, GCB-like tumors exhibit high expression of components of the interleukin 4 (IL-4) signaling pathway and of IL-4 target genes such as BCL6 and HGAL, whose high expression independently predicts better survival.

These observations suggest distinct activity of the IL-4 signaling pathway in DLBCL subtypes.

Herein, we demonstrate similar IL-4 expression but qualitatively different IL-4 effects on GCB-like and ABC-likeDLBCL.

These differences in tyrosine phosphatase expression might underlie distinct expression profiles of some of the IL-4 target genes and could contribute to a different clinical outcome of patients with GCB-like and ABC-like DLBCLs.

[Source] The source of this record is MEDLINE®, a database of the U.S. National Library of Medicine.

[Title] Pediatric diffuse large B-cell lymphoma demonstrates a high proliferation index, frequent c-Myc protein expression, and a high incidence of germinal center subtype: Report of the French-American-British (FAB) international study group.

BACKGROUND: Diffuse large B-cell lymphoma (DLBCL) makes up 10-20% of pediatric non-Hodgkin lymphoma, and these patients have a significantly better prognosis than adults with DLBCL.

The difference in prognosis may be related to clinical, phenotypic, and/or biological differences between adult and pediatric DLBCL.

In adult DLBCL, the germinal center (GC) phenotype is associated with a better prognosis than the activated B-cell (ABC) phenotype.

However, a high proliferative index and expression of Bcl2 and c-Myc protein have all been associated with worse outcomes.

While multiple studies have addressed the phenotype and expression patterns of adult DLBCL, relatively little is known about these biological variables in pediatric DLBCL.

The goal of this study was to investigate the proliferative index, the relative frequencies of the GC and non-GC subtypes, and the expression of Bcl2 and c-Myc protein in a cohort of children with DLBCL treated in a uniform manner.

PROCEDURE: We performed immunohistochemistry (IHC) for MIB1, CD10, Bcl6, MUM1, Bcl2, and c-Myc on DLBCL tissue from children treated uniformly in the FAB LMB96 trial (SFOP LMB96/CCG5961/UKCCSG/NHL 9600).

CONCLUSIONS: These findings suggest that there are significant biologic differences between pediatric and adult forms of DLBCL, which may contribute to the superior prognosis seen in the pediatric population relative to adult disease.

[Source] The source of this record is MEDLINE®, a database of the U.S. National Library of Medicine.

Diffuse large B-cell lymphomas (DLBCLs) can be classified into two subtypes: germinal-centre B-cell (GCB)-like and Activated B-cell (ABC)-like tumours, which are associated with longer or shorter patient overall survival, respectively.

In our previous studies, we have shown that, although DLBCL tumours of GCB-like and ABC-like subtypes express similar levels of IL4 mRNA, they exhibit distinct patterns of IL-4-induced intracellular signalling and different expression of IL-4 target genes.

We hypothesized that these differences may contribute to the different clinical behaviour and outcome of DLBCL subtypes.

Herein, we demonstrated that IL-4 increased the sensitivity of GCB-likeDLBCL to doxorubicin-induced apoptosis and complement-dependent rituximab cell killing.

In contrast, IL-4 protected ABC-likeDLBCL from the cytotoxic effects of doxorubicin and rituximab.

The distinct effects of IL-4 on doxorubicin sensitivity in GCB-like and ABC-likeDLBCL cells may be partially attributed to the contrasting effects of the cytokine on Bcl-2 and Bad protein levels in the DLBCL subtypes.

These findings suggest that the different effects of IL-4 on chemotherapy and immunotherapy-induced cytotoxicity of GCB- and ABC-likeDLBCL could contribute to the different clinical outcomes exhibited by patients with these two subtypes of DLBCL.

[Source] The source of this record is MEDLINE®, a database of the U.S. National Library of Medicine.

The combined use of the array CGH data with gene expression profiling and specific gene rearrangement analyses further delineated the subtype-specific genomic alterations.

For instance, we revealed that activated B-cell-likeDLBCL is characterized by a gain of chromosome 3, 18q and loss of 9 p21, whereas the germinal center B-cell-likeDLBCL is characterized by a gain of 2p15, 7q, and 12q.

Among these genomic alterations,we found the 9 p21 loss (p16INK4a locus) to be the most aggressive type of DLBCL.

In this study we show that heat stress inhibits constitutive NF-kappaB DNA-binding activity in different types of B-cell malignancies, including multiple myeloma, activated B-cell-like (ABC) type of diffuse large B-cell lymphoma (DLBCL) and Burkitt's lymphoma presenting aberrant NF-kappaB regulation.

Altogether, the results indicate that aggressive B-cell malignancies presenting constitutive NF-kappaB activity are sensitive to heat-induced apoptosis, and suggest that aberrant NF-kappaB regulation may be a marker of heat stress sensitivity in cancer cells.

Here, we show with the use of an assay that measures DNA methylation levels of 50,000 CpG motifs distributed among more than 14,000 promoters that these 2 DLBCL subtypes are also characterized by distinct epigenetic profiles.

DNA methylation and gene expression profiling were performed on a cohort of 69 patients with DLBCL.

Apoptosis after HH signaling inhibition in DLBCL cells of ABC type was associated with downregulation of BCL2; however HH inhibition was not associated with BCL2 downregulation in DLBCL of GC type.

We also showed that DLBCL cells synthesize, secrete and respond to endogenous HH ligands, providing support for the existence of an autocrine HH signaling loop.

Our findings provide novel evidence that dysregulation of HH pathway is involved in the biology of DLBCL and have significant therapeutic implications as they identify HH signaling as a potential therapeutic target in DLBCL, in particular for those lymphomas expressing the HH receptor smoothened.

[Source] The source of this record is MEDLINE®, a database of the U.S. National Library of Medicine.

[Title] [Primary diffuse large B-cell lymphoma of central nervous system belongs to activated B-cell-like subgroup: a study of 47 cases].

OBJECTIVE: To investigate the histogenetic origin of primary central nervous system diffuse large B-cell lymphoma (DLBCL) with respect to the stage of B-cell differentiation, and identification of the relevant prognostic markers.

No significant correlation of the classification and FOXP1 expression found on the outcome (P=0.279 and P=0.154).

CONCLUSIONS: Most primary central nervous system DLBCL are shown belonging to the ABC subgroup, suggesting that primary central nervous system DLBCL is quite similar to a DLBCL subset, which is derived from late GC to early post-GC B cell.

The classification and FOXP1 expression do not show prognostic value in primary central nervous system DLBCL.

[Source] The source of this record is MEDLINE®, a database of the U.S. National Library of Medicine.

[Title]Diffuse large B-cell lymphoma in pediatric patients belongs predominantly to the germinal-center type B-cell lymphomas: a clinicopathologic analysis of cases included in the German BFM (Berlin-Frankfurt-Munster) Multicenter Trial.

Diffuse large B-cell lymphoma (DLBCL) in adults is a heterogeneous disease.

Biologic subgroups of DLBCL with a favorable prognosis (germinal center B-cell-like, GCB) and with a poor prognosis (activated B-cell-like, ABC) have been defined by gene expression profiling and can be distinguished by immunohistochemistry.

In contrast to their adult counterparts, children with DLBCL have an excellent prognosis.

We analyzed 63 cases of DLBCL in pediatric patients by immunohistochemistry and fluorescence in situ hybridization (FISH) and found a striking predominance of a GCB subtype, which might explain the good clinical outcome in these lymphomas.

Interestingly, FISH applied to 50 of these cases, as well as conventional cytogenetics available in 3 cases, revealed absence of the translocation t(14;18) involving the BCL2 gene, which is present in about 15% of adult GCB subtype DLBCL.

Our data indicate that pediatric DLBCL differs from adult DLBCL and might comprise a biologically unique subgroup of DLBCL from which important insights into the pathogenesis and biology of this disease might be gained.

[Source] The source of this record is MEDLINE®, a database of the U.S. National Library of Medicine.

[Title] Protein expression and cellular localization in two prognostic subgroups of diffuse large B-cell lymphoma: higher expression of ZAP70 and PKC-beta II in the non-germinal center group and poor survival in patients deficient in nuclear PTEN.

Patients diagnosed with diffuse large B-cell lymphoma (DLBCL) show varying responses to conventional therapy, and this might be contributed to the differentiation stage of the tumor B-cells.

De novo DLBCL cases were divided into two subgroups, the germinal center (GC) group (14/28) and the non-germinal center (non-GC) or activated B-cell (ABC) group (14/28).

Also, the subcellular localization of PKC-beta I and II differed in DLBCL cells, with the PKC-beta I isoform being expressed in both the cytoplasm and nucleus, while PKC-beta II was found exclusively in the cytoplasm.

In addition, five cell lines of DLBCL origin were analyzed for protein expression and for mRNA levels of PTEN and SHP1.

For the first time, we show that ZAP70 is expressed in a higher percentage of tumor cells in the aggressive non-GC subgroup of DLBCL and that PKC-beta I and II are differently distributed in the two prognostic subgroups of de novo DLBCL.

[Source] The source of this record is MEDLINE®, a database of the U.S. National Library of Medicine.

[Title] Immunophenotype and intermediate-high international prognostic index score are prognostic factors for therapy in diffuse large B-cell lymphoma patients.

BACKGROUND: The development of gene expression profiling and tissue microarray techniques have provided more information about the heterogeneity of diffuse large B-cell lymphoma (DLBCL), enabling categorization of DLBCL patients into 3 prognostic groups according to cell origin (but independently from the International Prognostic Index [IPI] score): germinal center (GCB), activated B-cell (ABC), and not classified (NC) diffuse large B-cell lymphoma.

This study investigated the role of immunohistochemical discrimination between GCB and ABC&NC-DLBCL subtypes in identifying those high-risk patients who may benefit from a more aggressive first-line therapeutic approach.

METHODS: From February 2003 to August 2006, 45 newly diagnosed DLBCL patients, with IPI≥2, were considered eligible for this study: 13 had a GCB, 8 an ABC, and 24 a NC-DLBCL.

Increased nuclear dephosphorylation of phospho-STAT6 (pSTAT6) was observed in ABC-like tumors, which exhibited a different expression profile of protein tyrosine phosphatases (PTPs).

Among the differentially expressed PTPs, only T-cell PTP (TCPTP) localizes to the nucleus.

Herein, we report that the elevated expression of TCPTP in ABC- versus GCB-likeDLBCL tumors is not due to the distinct ontogeny of these neoplasms but rather may be an acquired feature of the tumors.

Taken together, these results identify TCPTP as a physiological regulator of STAT6 phosphorylation and suggest that specific increases in TCPTP expression in ABC-like DLBCLs may contribute to the different biological characteristics of these tumors.

Using microarray analysis on prototypic cell lines, we identified microRNAs (miR-155, miR-21 and miR-221) that were more highly expressed in ABC-type than GCB-type cell lines.

Consistent with the cell line model, expression levels were higher in DLBCL cases with an ABC-type immunophenotype than those that were GCB-type (p < 0.05).

Moreover, using multivariate analysis we found that expression of miR-21 was an independent prognostic indicator in de novo DLBCL (p < 0.05).

Interestingly, expression levels of both miR-155 and miR-21 were also higher in nonmalignant ABC than in GCB cells.

As we also demonstrate that expression of microRNAs can be measured reliably from routine paraffin-embedded biopsies of more than 8-years-old (p < 0.001), we suggest that microRNAs could be clinically useful molecular markers for DLBCL as well as other cancers.

[Source] The source of this record is MEDLINE®, a database of the U.S. National Library of Medicine.

Diffuse large B-cell lymphoma (DLBCL) responds well to treatment with CHOP and the R-CHOP regimen, but a subset of patients still fail to achieve complete or durable responses.

Recent advances in gene expression profiling have led to the identification of three different subtypes of DLBCL, and confirmed that patients with the activated B-cell (ABC) disease subtype are less likely to respond well to CHOP-based regimens than those with germinal centre B-cell-type (GCB) disease.

This discovery could herald the use of gene expression profiling to aid treatment decisions in DLBCL, and help identify the most effective management strategies for patients.

Treatment options for patients with relapsed or refractory DLBCL are limited and several novel agents are being developed to address this unmet clinical need.

Novel agents developed to treat plasma cell disorders such as multiple myeloma have shown promising activity in patients with NHL.

Indeed, the immunomodulatory agent lenalidomide and the proteasome inhibitors bortezomib and carfilzomib, as single agents or in combination with chemotherapy, have already demonstrated promising activity in patients with the ABC subtype of DLBCL.

In general, c-REL nuclear expression did not correlate with GCB vs. non-GCB phenotype, International Prognostic Index score, or OS.

However, cases with a GCB phenotype and negative nuclear c-REL demonstrated better OS than cases with a GCB phenotype and positive nuclear c-REL (KMS analysis, p = 0.045, Breslow-Gehan-Wilcoxon test), whereas in cases with non-GCB phenotype, the expression of c-REL did not significantly impact the prognosis.

These results suggest that c-REL nuclear expression may be a prognostic factor in DLBCL and it may improve patient risk stratification in combination with GCB/non-GCB phenotyping.

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OBJECTIVE: To investigate the role of bcl-6 gene rearrangement and bcl-6 expression in three molecular subgroups of diffuse large B-cell lymphoma (DLBCL) and its clinicopathological significance.

Fluorescence in situ hybridization (FISH) was performed to detect the bcl-6 gene rearrangement and immunohistochemistry (EnVision method) was used to evaluate the expression of bcl-6, Ki-67, cyclin D3, Geminin and P27(Kip1) proteins in DLBCL.